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SKI pathways inducing progression of human melanoma

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Abstract

The proteins SKI and SnoN are implicated in processes as diverse as differentiation, transformation and tumor progression. Until recently, SKI was solely viewed as a nuclear protein with a principal function of inhibiting TGF-β signaling through its association with the Smad proteins. However, new studies suggest that SKI plays additional roles not only inside but also outside the nucleus. In normal melanocytes and primary non-invasive melanomas, SKI localizes predominantly in the nucleus, whereas in primary invasive melanomas SKI displays both nuclear and cytoplasmic localization. Intriguingly, metastatic melanoma tumors display nuclear and cytoplasmic or predominantly cytoplasmic SKI distribution. Cytoplasmic SKI is functional, as it associates with Smad3 and prevents its nuclear localization mediated by TGF-β. SKI can also function as a transcriptional activator, targeting the β -catenin pathway and activating MITF and NrCAM, two proteins involved in survival, migration and invasion. Intriguingly, SKI appears to live a dual life, one as a tumor suppressor and another as a transforming protein. Loss of one copy of mouse ski increases susceptibility to tumorigenesis in mice, whereas its overexpression is associated with cancer progression of human melanoma, esophageal, breast and colon. The molecular reasons for such dramatic change in SKI function appear to result from new acquired activities. In this review, we discuss the mechanisms by which SKI regulates crucial pathways involved in the progression of human malignant melanoma.

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Authors and Affiliations

  1. Department of Pathology, Baylor College of Medicine, Houston, TX, USA

    Jon A. Reed

  2. Department of Dermatology, Baylor College of Medicine, Houston, TX, USA

    Jon A. Reed & Estela E. Medrano

  3. Huffington Center on Aging, Baylor College of Medicine, Houston, TX, USA

    Qiushi Lin, Dahu Chen & Estela E. Medrano

  4. Departments of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    Estela E. Medrano

  5. Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA

    I. Saira Mian

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  1. Jon A. Reed
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Correspondence to Estela E. Medrano.

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Reed, J.A., Lin, Q., Chen, D. et al. SKI pathways inducing progression of human melanoma. Cancer Metastasis Rev 24, 265–272 (2005). https://doi.org/10.1007/s10555-005-1576-x

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